Infusions with molsidomine and isosorbide-5-mononitrate in congestive heart failure: mechanisms underlying attenuation of effects.
The use of nitrates for treatment of heart failure is encumbered by tolerance, caused by whatever mechanism, which has been reported only in a few instances with sydnonimines. Accordingly, we compared molsidomine (6 mg/h) and isosorbide-5-mononitrate (3.75 mg/h) with respect to maximal hemodynamic effects, rapidity and extent of attenuation, and underlying mechanisms by means of constant infusions over 24 h each in 15 patients with chronic congestive heart failure (NYHA II-III) with a placebo-controlled, double-blind, randomized, crossover protocol. Hemodynamic measurements and determinations of neurohormones were performed at baseline and at 2, 8, and 24 h after the beginning of infusions. With molsidomine, reductions of diastolic pulmonary artery pressure by 29% (p < 0.001), by 24% (p < 0.01), and by 24% (p < 0.01) versus placebo were found at 2, 8, and 24 h, which amounted to 19% (p < 0.01), 10% (NS), and 14% (NS) with the nitrate. Cardiac output was meaningfully affected only with molsidomine (+5%, NS, at 2 h; +9%, p < 0.05, at 8 h; and +15%, p < 0.05, at 24 h), as was systemic vascular resistance (-13%, p < 0.05; -9%, NS; and -18%, p < 0.01) at the corresponding times. Increases in renin activity amounted to 130% (p < 0.001), 117% (p < 0.001), and 112% (p < 0.001) with molsidomine, and to 14, 16%, and 0 (each NS) with the nitrate at the corresponding times. Hematocrit was reduced by 5% (p < 0.001), 7% (p < 0.001), and 12% (p < 0.01) with molsidomine and by 5% (NS), 5% (p < 0.05), and 5% (NS) with the nitrate. We conclude that neurohumoral counterregulation or fluid shift, which is even more pronounced with molsidomine despite longer-lasting effects, has no essential role in nitrate-tolerance development. With molsidomine, such a role cannot be ruled out, although alternatively, a fluid shift from arterial to the low-pressure arm of circulation during the later course of infusion would be even more likely.
Lehmann
G
G
Deutsches Herzzentrum München, Klinik an der Technischen Universität, Munich, Germany.
Hähnel
I
I
Reiniger
G
G
Lampen
M
M
Beyerle
A
A
Schömig
A
A
D000328:Adult; D000368:Aged; D000450:Aldosterone / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D004311:Double-Blind Method; D004361:Drug Tolerance; D005260:Female; D018495:Fluid Shifts / Q000187:drug effects; D006325:Heart Atria / Q000187:drug effects / Q000503:physiopathology; D006333:Heart Failure / Q000188:drug therapy*; D006339:Heart Rate / Q000187:drug effects; D006400:Hematocrit; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D007548:Isosorbide Dinitrate / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D008981:Molsidomine / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D018377:Neurotransmitter Agents / Q000097:blood; D011651:Pulmonary Artery / Q000187:drug effects / Q000503:physiopathology; D012083:Renin / Q000097:blood; D013997:Time Factors; D014655:Vascular Resistance / Q000187:drug effects; D014665:Vasodilator Agents / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D016277:Ventricular Function, Left / Q000187:drug effects
D018377:Neurotransmitter Agents; D014665:Vasodilator Agents; D000450:Aldosterone; D008981:Molsidomine; D012083:Renin; D007548:Isosorbide Dinitrate; C030397:isosorbide-5-mononitrate